Design, Synthesis, Biological Evaluation of New Porphyrin and Metalloporphyrin Derivatives

Abstract In our research, we produced some novel porphyrin derivatives 4a–g in high yields. We also synthesized and characterized some of their metalloporphyrin complexes 5–11. The structures of these novel porphyrins were assured by spectroscopic techniques. The geometric structure and magnetic properties of metallo-porphyrins 5–11 have also been studied. Antiviral and antitumor activities were estimated and the structures activity relationships were accomplished. The Porphyrin derivatives 4g, 4f, 9, 10 and 11 displayed strong antiviral activity for HSV-1 compared to Aphidicoline as reference. While derivatives 4g and 6 exhibited very strong activity against HIV-1. Porphyrin derivatives 4g, 6, 9, and 10, in general, displayed strong activity against all the tested human cell lines.


Introduction
Porphyrins (Ps) and metallo-porphyrins are important class of compounds that display a diversity of pharmacological activities. [1][2][3][4][5] Numerous water-soluble polysulphonated and polycarboxylated porphyrin compounds, as well as specific metalated end products of these compounds, have been synthesized and tested for antiviral activity against human immunodeficiency viruses (HIV-1 and HIV-2), simian immunodeficiency and many different viruses. Surrounded by the drugs approved in the US for clinical usage in the treatment of patients with AIDS, there are five dideoxynucleoside equivalents: azidothymidine (AZT), didanosine (ddI), zalcitabine (ddC), stavudine (D4T) and lamivudine (3TC). 6,7 Further, most of these drugs show some severe poisonous side-effects, and the fast appearance of resistant human immunodeficiency virus type 1 (HIV-1) alternatives should be a limitation to their clinical worth. Therefore, novel molecules are wanted for the treatment of AIDS patients and asymptomatic seropositive HIV carriers. 8 The synthesis of porphyrins makes a chance for manipulation to modify the physical and chemical properties and the potential for light initiation. Hematoporphyrin derivative (HPD) deactivates the enveloped viruses herpes simplex, HSV, and cytomegalovirus. The benzoporphyrin derivative (BPD) is extremely effective against enclosed viruses but significantly less effective against nonenveloped viruses. 9 Porphyrin derivatives (PD) are widely applied in cancer treatment because these molecules have both therapeutic and diagnostic properties. Although, porphyrins showed powerful phototherapeutic effects such as (photodynamic therapy and photothermal therapy), 10 they also display excellent behavior toward antitumor effect. Cancer remains one of the main causes of human death, despite the great human forces and resources that have been devoted to combating it. Until now, the treatment efficacy of ancient cancer treatment methods (surgery, chemotherapy, and radiotherapy) remains unacceptable for several kinds of cancer. 11 A number of porphyrins and their derivatives have been tested to have activity against HIV, vaccinia, and coronavirus. Porphyrin based compounds were suggested to inhibit virus infection by reducing the fusogenic potential of the virus. 12 However, the mechanism of action of porphyrin-based compounds is not well understood. While current anti-herpes agents target viral DNA replication, interference with the upstream replicative events such as fusion would not adversely affect the host cell metabolism, and makes them important targets for chemotherapeutic intervention of virus dissemination.
At present, modified nucleosides or their prodrugs are the most commonly used antiherpetic drug. The mechanism of their action is related to DNA polymerase suppression. In this way, it is important to find more biologically active compounds from different classes that could be used as anti-herpes drugs and to find out how they work. 13 Porphyrins are a unique class of heterocyclic tetra-pyrrolic molecule. They play an essential role in vital biological processes of energy conversion and oxygen transfer. Due to their unique photophysical properties, this class of compounds is of interest because they can be used in a wide range of ways in medicine and technology.
Synthetic porphyrins with positive-charged groups have shown antiviral and antibacterial effects. 14,15 The cationic charge of the molecule promotes the electrostatic binding of porphyrin to the outer surface of the bacterial cell. DNA is also one of the most specific biological targets for cationic porphyrins. It has been said that these compounds form strong complexes with nucleic acids, which can be used to recognize non-canonical structures of DNA called Gquadruplexes. 16 In the current work, new amphiphilic cationic meso-arylporphyrins containing pyridinium residues at the periphery of the macrocycle were synthesized and their antiviral effect against HSV-1 was investigated.
There are many difficulties during the preparation of functional porphyrins such as separation, purification and limited availability of precursors. 17 Acid-catalyzed reaction of dipyrromethanes with proper aldehydes is the key to the construction of porphyrins, which is reported in much research. 18 Commonly, formylation process followed by transformation to new functional groups has an important role in synthesis of porphyrins bearing one carbon unit directly attached to the meso-positions. 19 First, the production of porphyrins in low yields by using the Rothemund and Adler-Longo methods 20,21 is due to the harsh reaction conditions. In addition, it wasn't possible for the formation of porphyrins carrying sensitive function groups. Based on these disadvantages, the achievement of porphyrin formation under gentle conditions became an understandable requirement. Furthermore, these mild conditions were also required for obviation of the side reactions, which lead to undesired by-products.
In addition to the above realities, complexes with Cu, Fe, and Zn can catalyze various types of interesting reactions in organic synthesis. A number of complexes emulate the action of numerous heme enzymes such as cytochrome P450, and lignin peroxidase. 22,23 Metalloporphyrins are also served as catalysts in water splitting for the production of hydrogen and oxygen. 24 Metalloporphyrins have been also investigated as sensors. 25 In our research, the novel meso-tetrakis phenoxyacetamido porphyrins and their Cu, Zn, and Fe complexes, which act for pharmacological screening as antiviral and antitumor agents, have been synthesized and reported for the first time.

Synthesis and characterization
In our work, we reported the synthesis of some novel 2-(4-formylphenoxy)-acetamide derivatives (Scheme 1) to give novel free base porphyrin derivatives 4a-g (Scheme 2) and certain of their metal complexes 5-11 (Scheme 3) which were evaluated as antiviral and antitumor agents.
The chloroacetylation of primary amines in water (basic or neutral conditions) is considered as a key for the formation of functionalized a-chloroacetamides (Schotten-Baumann conditions). 26 There is a great interest of halogenated acid derivatives due to their promising acidity which eliminate or inhibit the growth of bacteria, viruses fungi or parasites. 27 N-Aryl 2-chloroacetamides have attracted a great interest because of their antimicrobial activity like herbicides, disinfectant and antifungal. 28,29 Also, 2-chloroacetamides were used in solid-state chemistry, 30 natural and pharmacologically favorable products and biomarkers. [31][32][33][34] Herein we report the reaction of N-aryl chloroacetamide derivatives 2a-g with 4-hydroxybenzaldehyde in DMSO in presence of KOH to generate 2-(formylphenoxy)-N-aryl-acetamides 3a-g (Scheme 1).
The major obstacle associated with the chemistry of porphyrin is the low yield reaction. Although the plentiful synthetic methodologies for porphyrins and its derivatives have been previously reported. 35,36 Because of low reaction yield, we employed a novel synthetic approach followed by purification using the literature methods. Chan et al. reported the technique of column chromatography on silica gel (3:1 -CH 2 Cl 2 /hexane) for the purification, under this condition porphyrin could not be removed from the silica column. 37 Using silica gel (1.5:1 -CHCl 3 /hexane) modified the chromatographic conditions and improved purification. In recent times, there is a novel synthetic technique which gives 80-90% yield with minimal chromatography by using Fadda et al.. 38 The key to our accomplishment is the usage of a capping mechanism which avoids the formation of polymeric pyrroles. About the capping mechanism, we propose to usage dimethylformamide as a solvent (Schemes 2 and 3).
Meso-substituted porphyrin derivatives 4a-g have been prepared from the reaction of their corresponding aldehydes 3a-g with pyrrole in existence of p-toluenesulfonic acid as indicated in Scheme (2). This mechanism containing acid-catalyzed addition of pyrrole to the targeted aromatic aldehyde followed by dehydration that lead to the formation of porphyrin moiety. Ring Scheme 1. The synthesis of N-aryl-2-(formylphenoxy)acetamides 3a-g closure leads to the formation of the reduced form of porphyrin (porphyrinogen), followed by oxidation to give the porphyrin blocks. The suggested capping mechanism is listed in Scheme (3). The existence of dimethylformamide makes a reversible cap forms that protects this intermediates, during the reaction with pyrrole.
Structures of porphyrins 4a-g were confirmed from their correct spectral analyses. The 1 H NMR spectra of porphyrins 4a-e showed a characteristic singlet signal, in general, around the range of d 2.71 ppm for the NH proton, singlet at d 4.63 ppm due to four aliphatic CH 2 protons, doublet signals centered at d 5.25, 5.61, 5.84 and 6.60 ppm due to eight pyrrolic protons. The multiplet at d 7.06-7.62 ppm was attributed to the aromatic protons, while the two singlet signals at d 10.03 and 10.16 ppm were assigned for the NH amidic proton in addition to one deshielded NH proton. 13 C-NMR showed an obvious characteristic signal at d 67.0 ppm to indicate the O-CH 2 carbons, 162.7 ppm due to ph-CH¼carbons and 166.6 ppm due to carbonyl carbons. Its UV-vis spectrum showed k max at 422 nm. 1 H NMR of porphyrin 4b; in addition to the probable Scheme 2. Classic synthetic way for the formation of porphyrin derivatives 4a-g. signals, there is a singlet signal at d 2.24 ppm due to protons of four CH 3 groups. 13 C NMR exhibited a characteristic signal at d 20.4 ppm due to four CH 3 carbons. Its UV-vis spectrum revealed k max at 432 nm.
The expected picture of 1 H NMR spectrum of porphyrin 4c displayed the expected general picture of porphyrin, plus singlet at d 3.70 ppm due to four OCH 3 protons. 13 C-NMR displayed an obvious characteristic signal at d 55.1 and 166.1 ppm due to OCH 3 and carbonyl carbons respectively. Its UV-vis spectrum revealed k max at 422 nm. 13 C NMR spectrum of porphyrin 4d exhibited an observable characteristic signal at d 133.7 ppm due to C-Cl carbons. Its UV-vis spectrum showed k max at 420 nm. 1 H NMR spectrum of porphyrin 4e showed the general spectrum similar to 4a in which the expected area of aromatic protons displayed multiplet signals due to forty four protons. 13 C NMR spectrum showed a characteristic signal at d 167.4 ppm due to carbonyl carbons. Its UV-vis spectrum displayed k max at 420 nm.
The specific concern for preparation of porphyrin bearing heterocyclic ring system is due to diverse biological, electronic properties and photophysical. A lot of nitrogen-containing heterocyclic porphyrins had been made, and their properties had been looked at. 39 Numerous pyridine and pyrazole derivatives were found to be associated with a broad range of biological activities including antimalarial, antibacterial, antitumor, and anti-inflammatory. 40 A flash-column with eluent form CH 2 Cl 2 and CH 3 OH (98:2) was used as the suitable method for purification of the porphyrins 4f and 4g. The 1 H NMR spectrum of porphyrin 4f revealed the proton at sixth position of pyridine as doublet at d 8.31 ppm. The UV-Vis spectrum of 4f was recognized at concentrations of 1 Â 10 À5 mol in DMF. Highly characteristic spectra were obtained for porphyrin derivatives 4f and 4 g in which the B band is displayed at k max ¼ 420 nm and Q bands are detected in range 420 À 488 nm. The IR spectra have a characteristic macro cyclic bending frequency of 1007 and 1054 cm À1 for porphyrin 4f and 4g respectively. 1 H NMR spectrum of porphyrin 4g displayed a characteristic singlet signals at d 2.10 and 3.10 ppm due to the protons of methyl and N-methyl in pyrazole ring, in addition to the other predictable picture of porphyrin protons. 13 C NMR exhibited signal at d 161.6 ppm for the carbonyl carbon of pyrazole ring and at 167.4 ppm due to amidic carbonyl carbons (Table 1).
In our work we used the traditional Alder two-step approach for the synthesis of metalloporphyrin. This way included the reaction of porphyrin and the suitable metal salt with heating under reflux using DMF as a solvent. However, this method has several disadvantages such as: the low yields of the obtained metalloporphyrins (<20%) besides it consumed a long reaction time during pyrrole polymerization process. So, we tried another way for the synthesis of new metalloporphyrins in high yields and less time of reaction. This way called, the one-pot reaction method using DMF which proved to be very successful when it act as a capping agent. In this method, the reaction progress started with refluxing pyrrole, a suitable aldehyde and the metal salt under N 2 gas for an equitable short time to give a range of metallo-porphyrins 5-11 in high yields reached to (82-87%). This yield is superior comparing with using the two-steps technique in which the porphyrin is synthesized separately and reacts with the metal salt (Scheme 3).
The IR spectra of porphyrins 4a, 4c and 4f exhibited a strong absorptions at (1599 and 1537) and 1602 cm À1 respectively due to t(C¼C) Pyrrole and t(C¼N) Pyrrole stretching vibration. It is expected that shifted t(C¼C) Pyrrole and t(C¼N) Pyrrole bands to minimize wave numbers due to coordination of the four N-pyrrole to the metal ion would decrease the electron density in the azomethine link. In the IR spectrum of porphyrin complexes 5-11, the t(C¼C) Pyrrole and t(C¼N) Pyrrole bands is shifted to the region at 1551-1568. Also the observed IR bands in the region of 1410-1431 cm À1 were assigned to t(C-C) Pyrrole and t(C-N) Pyrrole stretching vibrations in complexes. While, in ligands 4a, 4c and 4f, t(C-C) Pyrrole and t(C-N) Pyrrole stretching vibrations appeared at 1443, 1463, and 1469 cm À1 , respectively. During the complexation reaction, there was a decrease of 59-29 cm À1 and this is due to an increase the electron density of azomethine t(C¼N) linkage, which caused from p-electron movement from the metal to the nitrogen atom and delocalization interaction in porphyrin. These means that 4a, 4c and 4f act as a binegative tetradentate ligands for Zn II metal complex and mononegative tetradentate ligands in Cu II and Fe III metal complexes. The IR spectrum of the complexes appeared numerous bands in range 513 À 520 cm À1 due to (M-N) stretches. 41 The 1 H NMR spectroscopic data for 4a, 4f and their complexes in DMSO-d 6

Electronic and geometrical study of metalloporphyrin complexes 5-11
The electronic spectra of ligands 4a, 4c and 4f in DMSO showed bands near 422, 422 and 420 nm respectively. Because of the transitions of ligand to metal charge-transfer (LMCT) and weaker bands specified to d-d transitions, this caused the electronic spectrum of the complexes in DMSO in the range of 200-900 nm to contain intense bands. The intra-ligand charge transfer (n ! p Ã and p ! p Ã ) are specific for the transitions below 430 nm. 43,44 The magnetic moment of complexes 7, 8, and 11 is 5.1, 5 and 5.7 BM respectively expected for octahedral structures with 6 A 1g ground term. Its electronic spectrum of these complexes showed broad band at range 570-620 nm assigned to the 6 A 1g ! 4 T 2g ( 2 ) and 6 A 1g ! 4 E g (D) transition. The electronic spectra of complexes 5 and 9 exhibit bands near 538 and 536 nm and another bands near 650 and 922 respectively assigned to 2 B 1g ! 2 E g and 2 B 1g ! 2 B 2g , respectively. The band position with magnetic moments of 1.24 and 1.42 BM are consistent with square pyramidal structure. 45 The lower value may be due to little outcome of the diamagnetic ligands on the magnetic interaction due to the occurrence of two ligand molecules ( Table 2).
The solid ESR spectra of the Cu(II) complexes are given in Figures 1 and 2; spin Hamiltonian parameters, the G value and bonding parameters are calculated Table 3. The spectra exhibit axial symmetric g-tensor g ┴ > g jj ge (2.0023) for this complex, indicating that the unpaired electron is centered on the dx 2 -y 2 ( 2 B 1g ) orbital of the Cu II ion (dz 2 is ground term). 46 The g ┴ and g jj values are calculated from the spectrum using DPPH standard free radical as 'g' marker. The observed g jj value <2.3 suggesting an important covalent character of the metal-ligand bond in agreement with the literature observation. 47 The two g values (g ┴ > g jj ) are clearly indicated the penta-coordination about Cu(II) ion with a geometry intermediate between the trigonal bipyramidal and square pyramidal, however the closer geometry is square pyramidal limit with the four nitrogen atoms of porphyrin the around copper ion. The axial symmetry parameter G is given by the equation: G ¼ (gjj-2.0023)/(g ┴ -2.0023). 48 If G > 4, the exchange interaction is negligible between Cu(II) ions, while G ˂4 means a significant Cu-Cu interaction and tone straightly with measured magnetic moment. Hathaway 49 pointed out that for pure r-bonding, K jj ¼ K ┴ ¼ 0.77 and for in-plane p-bonding K jj <K ┴ , while for out-of-plane p-bonding K ┴ <K jj the following simplified idioms were used to calculate K jj and K ┴ : The calculated values K jj > K ┴ relation indicates for out of-plane p-bonding, where k o (spin-orbital coupling) ¼ À830 cm À1 for the free Cu II ion and 15384.6 cm À1 is the electronic transition energy.   High infection rates with viruses cause diseases for human and animal worldwide. Furthermore, presence of antiviral agents are purposed the key viral enzymes that are including in the process of repetition. The drugs with dissimilar forms of action and resistance profiles caused by amalgamation therapy could be valuable for a numeral of viral infections. Discovering novel agents with new antiviral mechanisms with wide spectrum of antiviral activities is urgent demand. Consequently, 14 novel compounds of porphyrin derivatives 4a-g and some of their metalloporphyrins 5-11 were estimated for their in vitro activity compared to viruses mentioned in (Tables  4 and 5). 50,51 Vero African green monkey kidney cells tested with the HSV-1, the antiviral Aphidicolin was utilized as a reference drug. 52 The cytotoxicity of the tested porphyrins was accomplished via Vero cell culture. 53 The evaluation of cytotoxicity displayed by IC 50, means 50% inhibition of cell proliferation by this concentration. The target compounds examined by plaque reduction assay for antiviral activity. Amongst the 14 novel compounds, 4g compound showed highest activity with minimum antiviral concentration (MAC) 0.03 m.M/L due to the reduction of number of the plaques by 48%. Otherwise, compounds 4f, 9, 10, and 11 displayed a good activity against HSV-1. Also, 4c, 4d, 5, 6, 7 and 8 display moderate activity against HSV-1. Compounds 4d, 4f, 4g, 5, 6, 7, 9, 10, and 11 showed the highest cytotoxicity (IC 50 0.1 mM/L). However the other compounds displayed the lowest cytotoxic activity (IC 50 >0.1 mM/L) as shown in (Figure 3, Table 4). Our findings demonstrated that these porphyrins entered the cells through the endocytotic pathway and were transported to lysosomes whose pH increased rapidly upon irradiation. Lysosomal damage did not cause any intracellular redistribution of the porphyrin and represented the primary event causing cell death, very likely via necrosis.

Antiviral activity (HIV-1)
One of the most important diseases caused by AIDS (immunodeficiency) due to elevated number of deaths. 54 Recently, the anti-HIV-1 drug designed for working at any stage of the virus reproductive cycle as the killing of T4 lymphocytes. 55 The average effective concentration (EC 50 ) of the confirmed compounds using infected cells was compared with their cytotoxic effect (IC 50 ) on uninfected cultures. While other culture treated with Azidothymidine (AZT), which was utilized as positive control. The HIV-1 in vitro evaluation confirmed that the evaluated compounds showed resonating effects as outlined in (Table 5). From Table 5, it was found that, compound   4g and 6 has the highest cytotoxic activity against HIV-1, whereas, the rest of compounds have good to moderate activity.

Cytotoxicity (anticancer screening)
In this study, our tested compounds were estimated in-vitro as inhibitors for different cell lines that mentioned in (Tables 6 and 7). Table 6 displayed the results of the tested compounds expressed by IC 50 . Porphyrin compounds 4g, 6, 9 and 10 showed the highest cytotoxic activity against HepG2 cell line. Porphyrin compounds 4d, 5, 7 and 8 have strong activity, where compounds 4a, 4b, 4c, 4f and 11 have a moderate activity against the target cell line. Furthermore, compound 4g displayed the maximum cytotoxic activity against the WI-38 cell line while, the rest of the other compounds showed a range from strong to moderate cytotoxic activity. However compound 4e showed weak activity. Moreover, compounds 4g, 6, 9 and 10 displayed the maximum activity against MCF-7 cell lines. The other compounds revealed moderate activity with the exception of compounds 4b and 4e displayed weak activity against the same cell line. All compounds displayed moderate cytotoxicity against Vero cell lines, excluding compounds 4g, 6 and 9, which displayed strong activities. While compound 4e showed weak activity. Structure activity correlation, the results of porphyrins and their metalloporphyrin derivatives correlated with structure variation and modification. DNA is made of four nucleotides. There are four forms of nitrogen bases present in nucleotides: Adenine (A), Thymine (T), Guanine (GUA) and Cytosine (C). It was present that Adenine almost linked to Thymine, on the other hand Guanine linked to Cytosine via H-bond. There are two factors which controlled of the cytotoxicity activity of the confirmed compounds toward any cell lines: 56,57 (1) The formation of intermolecular H-bond with any of one of the nucleotides in DNA. (2) The positive charge which confirmed on the tested compounds can attract with the negative charge on the cell wall. The following SAR was followed by making a comparison between the experimental cytotoxicity of the compound described in this study to their structures. Compound 4g exhibited the highest activity along the four targeted cell lines owing to the existence of NH and pyrazolyl moiety or forming H-bond with either one of nucleobases of the DNA and caused harm. Because of the presence of NH groups that can form the H-bond with one of the nucleotides of DNA and cause its harm, so all of the tested porphyrin complexes displayed strong to moderate activity. Likewise the presence of electron withdrawing chlorine atom in compounds 5, 7, 8, 9, and 11 converted these molecules to be positively charged forming electrostatic attraction with DNA nucleotides.

General remarks
1 H-NMR (500 MHz) and 13 C-NMR (125 MHz) spectra were measured on 500 MHz JOEL instrument (DMSO-d 6 is used as solvent). IR spectra were documented on a Mattson 5000 FTIR Spectrometer. Ultraviolet spectra were recorded using Unicam UV2 UV/Vis spectrometer. C, H and N elemental analyses were measured in the micro analytical unit, Cairo University, Faculty of Science.

Preparation of porphyrin compounds
3.2.1. General procedures for the preparation of chloroacetamide derivatives 2a-g To a mixture of different aromatic or heterocyclic amines 1a-g (0.03 mol) dissolved in acetone (25 mL), potassium carbonate (4.11 g, 0.03 mol) and chloroacetyl chloride (3.4 mL, 0.03 mol) was added and stirred for 4 hrs. The mixture was diluted with ice-cold water (75-80 mL). The precipitate was collected and recrystallized from ethanol to give different chloroacetamide derivatives 2a-g.

3.2.2.
General procedures synthesis of some new 2-(4-formyl phenoxy)-N-arylacetamide derivatives 3a-g A suspension of p-hydroxybenzaldehyde (1.22 g, 0.01 mol) and chloroacetamide derivatives 2a-g is dissolved in DMSO (25 mL) and K 2 CO 3 (2.1 g, 0.015 mol) was stirred for 4 hrs. The mixture was poured onto ice-cold water (75-80 mL) and kept in refrigerator for 6 hrs. The solid that collected by filtration was recrystallized from ethanol to produce the corresponding aldehyde derivatives 3a-g.
3-(4-Formylphenyl)-N-phenylpropanamide (3a) was isolated as beige crystals in 83% yield; m.p.   3.2.3. New methodology for the synthesis of new porphyrin derivatives 4a-g A mixture of aromatic or heterocyclic aldehyde (0.14 mol), pyrrole (0.14 mol) in dimethylformamide (35 mL) was placed in three necked flask (100 mL) fitted with nitrogen gas. The mixture was flashed for five minutes with nitrogen or helium gas and then refluxed for 10 min at 100 C. Then at p-toluene sulfonic acid (0.14 mol) in dimethylformmaide (10 mL). Within 1-2 min the reaction mixture turned to red color, then it was heated at 150 C for 1 hour. The proceeding of reaction was followed by UV-Vis, which characteristic band appeared in range of k max 415-430 nm the evidence of porphyrin formation. The mixture was poured into ice with stirring for 15 min, the obtained solid product was filtered off, dried and chromatography purified using CHCl 3 /hexane (1.5:1) on silica gel.

Antiviral properties
Anti-Herpes Simplex-1 Virus (HSV-1) and anti-Human Immunodeficiency Virus-1 (HIV-1) in vitro tests were performed as previously described in the literature. 59

Antitumor properties
Antitumor tests were carried out in the light of previously published work. 59

Conclusion
We synthesized the new porphyrin derivatives 4a-g in high yields (70-80% yields). Porphyrin derivatives 4a, 4c and 4e have been complexed successfully with various metal salts; Cu(g), Zn(g) and Fe(ł) using the traditional method besides the one pot reaction method. The one pot reaction method, helps us to obtain the corresponding metallo-porphyrins in high yields >80%. The key of our success is using the DMF as capping agent for pyrrole during the reaction which causing the relatively high yields for the synthesized novel porphyrins. Our novel porphyrin derivatives were screened for their pharmacology activities. In general, antiviral and antitumor evaluation showed that compound 4g as the highest activity.